Shc protein is known to be related to cell proliferation and carcinogenesis. However, the involvement of Shc in hepatocellular carcinoma (HCC) remains unknown. In the present study, we report that p46 Shc is probably expressed in the nuclei of hepatocytes and/or cancer cells during the development of HCC in Long-Evans Cinnamon (LEC) rats. The expression and localization of Shc in various pathological liver tissues obtained from LEC rats were analyzed by immunohistochemical study and Western blotting. Furthermore, tyrosine phosphorylation of Shc in various pathological liver tissues of LEC rats was studied by immunoprecipitation using a monoclonal anti-phosphotyrosine antibody. Although p66 Shc was detected in none of the liver tissues, regardless of pathological status, the expression of p46 Shc and that of p52 Shc increased proportionately with the development of HCC in LEC rats. Furthermore, although p52 Shc was localized only in the cytoplasm of hepatocytes and/or cancer cells, p46 Shc was found to express in both the nuclei and the cytoplasm of hepatocytes and/or cancer cells in precancerous and cancerous tissues of LEC rat liver. Tyrosine phosphorylation of p46 Shc and p52 Shc was detected only in cancer cells, and p46 Shc in such cells was much more heavily phosphorylated than p52 Shc. These results suggest that enhanced expression of p46 Shc and p52 Shc, as well as p46 Shc tyrosine phosphorylation, was involved not only in the process from normal liver to chronic hepatitis, but also in the transition from chronic hepatitis into HCC in LEC rats. Furthermore, unlike p52 Shc, p46 Shc was detected not only in the cytoplasm but also in the nuclei of hepatocytes (especially in transformed hepatocytes), and p46 Shc expressed in the nuclei may be closely related to hepatocarcinogenesis in LEC rats.

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